This application responds to RFA-AI-07-038 and seeks support for evaluating the use of the recombinant activated protein C (APC) in the treatment of radiation injury combined with inflammation and infection. APC has been already shown to reduce sepsis mortality in animal models and in human patients, and is approved for clinical use in the treatment of severe sepsis. Our preliminary data support the notion that APC protects hematopoietic stem cells from irradiation in vivo and thereby reduces mortality after whole body irradiation, possibly via mechanistically diverse effects on multiple organ systems, including: survival-promoting and anti-inflammatory effects on vascular endothelium and cytoprotective/proliferative effects on hematopoietic progenitors. These properties make APC therapy, which is already FDA approved for severe sepsis, an ideal candidate for the treatment of combined radiation injury. The R21 phase of this application will (1) provide proof-of-principle in a mouse model that APC administered as a single bolus infusion after lethal whole body radiation exposure can prevent lethality from bone marrow failure, in addition to lethality caused by lethal whole body radiation exposure compounded by subsequent infection;and (2) establish a dosing regimen to optimize overall efficacy and to expand the time window after which APC can be given following radiation exposure and still prevent mortality. The R33 phase of the study will (1) explore whether efficacy and safety of APC therapy can be further improved by the use of recombinant APC variants with selectively modified bioactivities, (2) generate evidence for the in vivo efficacy of human APC in the radioprotection of human hematopoietic cells transplanted into human xenograft-permissive NOG mice;and (3) generate evidence for the potential efficacy of post-exposure APC therapy in preventing death caused by gastrointestinal injury. Outcomes of the proposed studies will provide a strong incentive to further explore the clinical use of APC, and possibly safer recombinant APC variants with improved efficacy, as a life-saving treatment after lethal radiation exposure. In addition to developing APC as a safe and effective countermeasure against radiation combined injury, insights expected from these studies will lay a solid foundation for investigating the cellular and molecular basis of this entirely novel connection between the natural protein C anticoagulant pathway and protection of the hematopoietic system against radiation injury. This application evaluates the use of recombinant forms of the endogenous activated protein C (APC) molecule for the therapeutic prevention of bone marrow failure, infection, and ultimately mortality as they may occur after incidental whole body exposure to nuclear radiation. Outcomes of the study are expected to validate APC as a safe and effective treatment for victims of nuclear accidents and other threats involving radiation exposure.